Umbilical cord milking and delayed cord clamping for the prevention of neonatal hypoglycaemia: a systematic review and meta-analysis

Background Placental management strategies such as umbilical cord milking and delayed cord clamping may provide a range of benefits for the newborn. The aim of this review was to assess the effectiveness of umbilical cord milking and delayed cord clamping for the prevention of neonatal hypoglycaemia. Methods Three databases and five clinical trial registries were systematically reviewed to identify randomised controlled trials comparing umbilical cord milking or delayed cord clamping with control in term and preterm infants. The primary outcome was neonatal hypoglycaemia (study defined). Two independent reviewers conducted screening, data extraction and quality assessment. Quality of the included studies was assessed using the Cochrane Risk of Bias tool (RoB-2). Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Meta-analysis using a random effect model was done using Review Manager 5.4. The review was registered prospectively on PROSPERO (CRD42022356553). Results Data from 71 studies and 14 268 infants were included in this review; 22 (2 537 infants) compared umbilical cord milking with control, and 50 studies (11 731 infants) compared delayed with early cord clamping. For umbilical cord milking there were no data on neonatal hypoglycaemia, and no differences between groups for any of the secondary outcomes. We found no evidence that delayed cord clamping reduced the incidence of hypoglycaemia (6 studies, 444 infants, RR = 0.87, CI: 0.58 to 1.30, p = 0.49, I2 = 0%). Delayed cord clamping was associated with a 27% reduction in neonatal mortality (15 studies, 3 041 infants, RR = 0.73, CI: 0.55 to 0.98, p = 0.03, I2 = 0%). We found no evidence for the effect of delayed cord clamping for any of the other outcomes. The certainty of evidence was low for all outcomes. Conclusion We found no data for the effectiveness of umbilical cord milking on neonatal hypoglycaemia, and no evidence that delayed cord clamping reduced the incidence of hypoglycaemia, but the certainty of the evidence was low. Supplementary Information The online version contains supplementary material available at 10.1186/s12884-024-06427-w.

concentrations have shown to negatively affect neurological development [2].Therefore, strategies to prevent neonatal hypoglycaemia warrant investigation [5].
Waiting to clamp and cut the umbilical cord after the birth allows time for the transfer of blood in the placenta to the infant [6].Delayed cord clamping (DCC) has been shown to provide a variety of short-and longterm benefits for the infant.These include increased neonatal haemoglobin concentrations, decreased incidence of intraventricular haemorrhage (IVH) [7], prevention of hypotension, increased Apgar scores and decreased mortality [8][9][10][11].In preterm infants, DCC may reduce the risk of infant death by 27%, compared to early cord clamping (ECC) [11].Its unsurprising, therefore, that the World Health Organisation and American College of Obstetricians and Gynaecologists recommend DCC (> 1 min after birth) for improved infant health [12,13].
Umbilical cord milking (UCM) involves squeezing the umbilical cord several times from the placental end towards the infant [14,15].Since this technique can be completed quickly, it can provide an alternative placental transfusion in infants where DCC may be clinically inappropriate [14].A review by Basile et al. [16] which included randomised controlled trials (RCTs) as well as other study designs, showed that UCM may be comparable to DCC in its effect on haematological parameters.Two recent systematic reviews including only RCTs also found that UCM is comparable to DCC in improving short term haematological outcomes in babies ≥ 34 weeks gestation [15,17].In preterm infants, 2 g/dL higher initial levels of haemoglobin have been found in the UCM group compared to ECC or DCC groups [18], and there is some low quality evidence that UCM may improve developmental outcomes when compared to DCC in preterm infants [19].There appears to be no difference in risk of mortality for preterm babies receiving UCM compared to other cord management strategies [18], although the safety of UCM in extremely preterm infants remains unclear [20].
Once the cord is clamped and placental blood supply ceases, the newborn must adjust from dependence on their mother for fuel to initiating endogenous glucose production [21,22].Failure to adapt to this sudden interruption of glucose supply when the cord is clamped is the most common reason for neonatal hypoglycaemia [5,23].Placental transfusion through DCC or UCM provides extra blood and may potentially help protect against hypoglycaemia, but there is a paucity of information on this.Therefore, our objective was to perform a systematic review of the effects of DCC and UCM on the incidence of neonatal hypoglycaemia in both term and preterm infants.

Methods
This review was conducted by following the methodology outlined in the Cochrane Handbook for Systematic Reviews of Interventions [24] and is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines [25].This review was registered with the international database for prospective register of systematic reviews (PROSPERO) (ID: CRD42022356553).

Search strategy and selection criteria
We searched MEDLINE (Ovid), Embase (Ovid), CINAHL Plus, the Cochrane Central Register of Controlled Trials (CENTRAL), Current Controlled Trials (www.contr olledtrials.com), Clinical Trials (www.Clini calTr ials.gov), Australian and New Zealand Clinical Trials Registry (www.anzctr.org.au), and WHO ICTRP Search Portal (https:// apps.who.int/ trial search/), from inception until March 2023 (Appendix 1).Search results were imported into Covidence software [26] where titles and abstracts were independently screened for eligibility by two authors (EW,LR).Any disagreement was resolved by discussion or with a third author (LL).References of included studies were also screened for inclusion.
Inclusion criteria were term and preterm infants who underwent DCC (≥ 30 s, or study defined) compared to a control intervention (ECC, < 30 s or study defined) or UCM compared to a control intervention (other cord management strategies including ECC and DCC).We included published and unpublished RCTs without restrictions on language and publication date.Exclusion criteria included studies of only non-vigorous infants, or only those requiring resuscitation at birth.The eligibility of the studies was not based on reported outcomes.
The primary outcome was neonatal hypoglycaemia (study defined) before hospital discharge.Secondary outcomes were receipt of treatment for hypoglycaemia during initial hospital stay, number of episodes of hypoglycaemia during initial hospital stay, severity of hypoglycaemia (study defined), admission to special care nursery or neonatal intensive care unit (NICU), admission to special care nursery or NICU for hypoglycaemia, hypoglycaemic injury on brain imaging, blood glucose concentration during initial hospital stay, breastfeeding (study defined) at discharge, neurodevelopmental impairment (study defined), neonatal mortality, length of hospital stay, cost of intervention (as measured by study), and cost of neonatal care (as measured by study).

Data extraction
Data were extracted by two authors (EW, LR) using a custom-designed form on Covidence.Data extracted included study design, location, year of publication, population, intervention details, and information relating to control, participant baseline, outcomes, and subgroups.Any discrepancies in extracted data were resolved by consensus.Risk of bias for all outcomes was independently assessed by two authors (EW, LR) using the Cochrane Risk of Bias (RoB-2) tool [24,27].Any disagreements were resolved by consensus, and if necessary, by discussion with a third review author (LL).

Statistical analysis
Meta-analysis was undertaken separately for UCM and DCC using Review Manager 5.4.1.using random effect models [28].For dichotomous outcomes, the risk ratios (RR) with 95% confidence intervals (CIs) were calculated.For continuous outcomes, the mean differences (MD) with 95% CIs were calculated.All data using median values (range or interquartile range) were converted to mean and standard deviation (SD) using the method of Wan et al. [29].All glucose concentrations were converted to mmol/l.
The variability in effect estimates due to heterogeneity was determined by calculating the I 2 and X 2 for each analysis.Publication bias was determined by visual inspection of funnel plots, plotting the study effect size against the sample size, if there were enough studies (10 or more RCTs).If asymmetry was apparent, possible reasons were discussed.Direction of the findings tables were used to summarise the evidence if meta-analysis was not possible.
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [30] was used to assess the certainty of evidence for the following outcomes: (1) Neonatal hypoglycaemia (study defined); (2) Receipt of treatment for hypoglycaemia (study defined); (3) Severity of hypoglycaemia (study defined); (4) Admission to NICU for hypoglycaemia; (5) Length of initial hospital stay; (6) Breastfeeding (study defined) at hospital discharge.

Search results
The initial search identified 2 235 potential records, of which 1 596 were screened after duplicates were removed and 301 full texts were assessed for eligibility.Full text screening excluded 209 records.A total of 92 studies were included in the review, with data from 71 studies included in the final analysis (Fig. 1).Authors of ongoing/ unpublished studies were contacted to request current status or trial data but no unpublished data were available for inclusion.

Characteristics of included studies
There were 21 studies assessing UCM compared to control, 16 of which included preterm infants.Fourteen of these studies (67%) were conducted in high income countries, 3 in upper-middle income countries, and 1 in lower-middle income countries [31] (Table 1).They were conducted between 2007 and 2022, and sample size ranged from 24 to 253 infants.
Fifty studies compared DCC to control, of which 19 included preterm infants.Cord clamping delay varied from 30 s to 8 min.Twenty-two of these 50 studies were conducted in high-income countries (44%), 13 (26%) in upper-middle income countries, and 15 (30%) in lowmiddle income countries.They were conducted between 1988 and 2022, and sample size ranged from 32 to 1 566 infants (Table 1).

Risk of bias in included studies
In the studies assessing UCM, high risk of bias was found in 2/8 studies looking at length of hospital stay outcome (25%), and some concerns were found in 5/8 studies (63%).For neonatal mortality, 18% of studies (2/11) showed high risk of bias, and 64% (7/11 studies) had some concerns.Two of the 5 studies (20%) assessing neurodevelopmental outcomes had high risk of bias, and 1/5 (20%) had some concerns.Only one study assessed glucose concentrations, and this was found to have low risk of bias (Fig. 2).
In the studies assessing DCC, one study assessing hypoglycaemia had high risk of bias, and 4/6 (67%) had some concerns (Fig. 3).For admission to NICU some studies (43%) had some concerns, as did many of the studies assessing breastfeeding at discharge (60%).For glucose concentrations, none of the studies had high risk of bias but most (75%) had some concerns, as did those assessing length of stay (73%).For studies assessing neonatal mortality, many had high risk of bias (40%) or some concerns (53%).For neurodevelopmental outcomes, many studies had high risk of bias (46%) or some concerns (46%).

Primary outcome Hypoglycaemia
No studies reported the incidence of hypoglycaemia.
A further five studies assessed the effect of UCM on neurodevelopmental outcomes at various ages [36][37][38][39][40], but meta-analysis was not possible due to the heterogenous nature of the assessment methods and outcome interpretation.Of the five studies, one reported statistically significantly improved motor outcome after UCM at 18-22 months age [37].The remaining four studies reported no difference in developmental outcomes between the

Other outcomes
There were no data available for the effect of UCM on breastfeeding at discharge, incidence of hypoglycaemia, receipt of treatment for hypoglycaemia during initial hospital stay, number of episodes of hypoglycaemia, severity of hypoglycaemia, hypoglycaemic injury on brain imaging, NICU admission for hypoglycaemia, cost of intervention or cost of neonatal care.

Primary outcome Incidence of hypoglycaemia
Evidence from six studies [53][54][55][56][57][58] suggests that DCC may result in little to no difference in neonatal hypoglycaemia (444 infants, RR = 0.87, CI:0.58 to 1.30, p = 0.49, I2 = 0%, low certainty of evidence) (Fig. 8).The definition of hypoglycaemia was not specified in two studies, blood glucose concentrations of < 2.2mmol/L in the first 4 h and/ or < 2.5mmol/L at 3-24 h in two studies, < 2.0 mmol/L at 3 h in one study, and < 2.5mmol/L before a feed in one  One study included term infants, one late preterm infant and four included preterm infants (Table 1).

Admission to the neonatal intensive care unit for hypoglycaemia
DCC may result in little to no difference in admission to NICU for hypoglycaemia (RR 1. 95 (0.18, 21.35); p = 0.58).

Receipt of treatment for hypoglycaemia during initial hospital stay
DCC may not reduce the receipt of treatment for hypoglycaemia during initial hospital stay RR 0.14 (0.01, 2.68) p = 0.19.One study of women with gestational diabetes who gave birth to term infants (> 37 weeks gestation) [54] reported that no infants in the DCC group (cord Fig. 9 Effect of delayed cord clamping on blood glucose concentration Fig. 10 Effect of delayed cord clamping on admission to neonatal intensive care clamping 60 s after birth, n = 40) required (defined as glucose infusion) for hypoglycaemia, compared to three infants in the ECC group (cord clamped as early as possible, n = 40).This evidence was graded as low certainty.

Severity of hypoglycaemia
The same study [54] reported that 0/40 infants in the DCC group had severe hypoglycaemia (blood glucose < 1.4 mmol/l), compared to 2/40 (5%) in the ECC group.This evidence was graded as low certainty.DCC may not reduce incidence of severe hypoglycaemia RR 0.20 (0.01, 4.04); p = 0.29.
A further twelve studies [82][83][84][85][86][87][88][89][90][91][92] reported the effect of DCC on neurodevelopmental outcomes, but the methods of assessment and outcome reporting differed between studies, making it difficult to conduct a meta-analysis.Of the 12 studies, five reported statistically significantly improved outcome with DCC, whilst six reported no difference, and one reported a reduced score for personal-social development with DCC compared to ECC (Table 2).

Other outcomes
No data were available for the effects of DCC on hypoglycaemic injury on brain imaging, cost of intervention and cost of neonatal care.

Subgroup analysis
In subgroup analyses for gestational age (term vs preterm infants), timing of the cord clamping (30-60 s vs > 60 s), mother's diabetes status (yes/no), hospital setting, and delivery method (vaginal vs caesarean) there were no significant interactions between any of the subgroups the available outcome variables (Appendix 2).There was insufficient data on risk factors for hypoglycaemia to conduct this pre-planned sub-group analysis.

Certainty of evidence (GRADE assessment)
For UCM, the certainty of evidence was assessed as low for length of hospital stay and was downgraded one level due to some concerns of risk of bias in most of the studies, and one level for wide 95% CI and relatively low sample size (Table 3).There were no data for the effect of UCM on the other GRADE outcomes.
For DCC, the certainty of evidence was low for all GRADE outcomes due to some concerns of risk of bias (neonatal hypoglycaemia, breastfeeding at discharge), and wide 95% CI or small sample size (neonatal hypoglycaemia and length of hospital stay).No significant publication bias was detected for length of stay outcome based on the funnel plot (Appendix 3).Admission to NICU for hypoglycaemia, severity of hypoglycaemia and receipt of treatment for hypoglycaemia were all rated as low certainty due to data coming from a single study (Table 4).

Summary of main results
The two main placental transfusion strategies to improve red blood cell volume after birth are DCC and UCM.This systematic review included a total of 71 studies and data from 14 268 infants.Despite including more studies than all reviews to date [15,17,19,101,102], we found no evidence for the effect of UCM on incidence of hypoglycaemia, and only one small study showing no significant difference in blood glucose concentrations between UCM and DCC groups [32].In line with findings from previous reviews, we also found no significant differences in UCM compared to control groups for neonatal mortality or length of hospital stay [19,101,102], and no difference in risk of neurological impairment.However, data from large, well-designed studies for hypoglycaemia outcomes are lacking.
The benefits of DCC are well known, and delaying the cord clamp by 60-120 s is recommended as best practice in preterm and term infants [103].To the best of our  knowledge, this is the first systematic review to assess the effects of DCC on neonatal hypoglycaemia.We that DCC may have little to no effect on the incidence of hypoglycaemia or blood glucose concentration, or on rate of NICU admission and breastfeeding at discharge.We found low certainty evidence from one study [65] that DCC may result in little to no difference in admission to NICU for hypoglycaemia compared to ECC.Data from another study showed that DCC may not effect receipt of treatment for hypoglycaemia and or severity of hypoglycaemia, compared with ECC [54].
There is evidence from several systematic reviews that DCC improves haemoglobin, iron levels and initial arterial blood pressure as well as reducing the risk of IVH and need for resuscitation compared to ECC [6,8,11,[104][105][106].These effects also suggest that DCC has the potential to reduce hypoglycaemia, since many neonatal problems, including the need for resuscitation, hypotension and IVH, result in increased tissue glucose consumption.These effects also suggest that DCC may improve neurodevelopmental outcomes [107], However, we found no evidence that DCC altered either of these outcomes, possibly due to very limited data and substantial heterogeneity in study design.
This meta-analysis showed that DCC may reduce neonatal mortality (low certainty of evidence).This is in line with findings from studies of very preterm infants [108] and many similar reviews of preterm infants [104,105], as well as a recent Cochrane review of evidence in preterm infants (average RR: 0.73, 95% CI: 0.54 to 0.98, moderate certainty) [11].We also found no difference in length of hospital stay when comparing DCC with ECC (low quality of evidence).Although few systematic reviews to date have assessed this outcome, Li et al. [104] found that DCC reduced hospital stay by 3.79 days (95% CI = -4.16 to -3.42) compared to ECC.Their review included four studies of preterm infants only, which may account for the difference in findings.

Overall completeness and applicability of the evidence
Although this is the first study to synthesise the evidence for UCM and DCC and neonatal hypoglycaemia, there are several gaps in the data available for this review.Firstly, no data were found for the effect of UCM on our primary outcome of neonatal hypoglycaemia, and data were lacking for several other pre-specified secondary outcomes.Secondly, there was large heterogeneity in the intervention (UCM varied from 2-5 times for 10-20cm/s) and control (varied from ECC to DCC after 60 s) designs.
For DCC, six studies (444 infants) reported neonatal hypoglycaemia as an outcome, but the evidence was rated as low certainty due to concerns of bias and imprecision.There was considerable variation in the DCC (30 s to 8 min) versus control (immediately to 180 s) timing.However, subgroup analysis of timing of the cord clamping showed no significant interaction between the different timings.Optimal timing for screening blood glucose is uncertain, and in our review, for both UCM and DCC the timing of the measurement of blood glucose concentrations differed.For example, for the UCM study glucose was measured on admission, whilst for the DCC studies some measurements were taken at birth and others within the first 24 h.Since glucose concentrations change rapidly within the first few hours after birth [5,109], the timing of blood glucose concentration measurements may have contributed to variability in the findings.Likewise, measurement of neurological outcomes differed considerably among the studies, making synthesis and meta-analysis of the data challenging.In addition, only one study assessed the effects of DCC on neonatal hypoglycaemia outcomes such as severity, admission to NICU, and treatment received.This review also excluded studies of non-vigorous infants, and those requiring resuscitation, therefore the evidence may not be generalisable to this population.

Quality of the evidence
The certainty of evidence was graded as low for all specified outcomes.As with most placental transition interventions [11], blinding the clinicians to the allocated intervention is not possible, although some studies did blind the outcome measurement.For many of the UCM studies, the sample sizes were small leading to imprecision.Similarly, many of the studies comparing the incidence of hypoglycaemia between DCC and ECC groups had small sample sizes.For many other neonatal hypoglycaemiarelated outcomes, data were only available from one study.

Quality of the review
To the best of our knowledge, this is the first review to investigate the impact of UCM and DCC on neonatal hypoglycaemia as a primary outcome.The large number of RCTs included in the review, more than any other review of UCM or DCC, is a key strength.However, the review does have certain limitations.Firstly, no data were found for the effects of UCM on incidence of hypoglycaemia, and only one study reported blood glucose concentrations.There was more evidence for the effects of DCC, with six studies assessing incidence of hypoglycaemia and eight studies measuring blood glucose concentrations.However, sample sizes were small, and the CIs were relatively large, therefore the results need to be interpreted with caution.Secondly, although there is potential for bias within the review process, we did take steps to minimise this by using at least two authors to independently screen, extraction, and assessment of quality.A third author was included for any discrepancies.

Conclusion
Data are lacking from large, well-designed studies assessing the effects of various placental transfusion strategies on neonatal hypoglycaemia.We found no studies assessing the effects of UCM on neonatal hypoglycaemia, and no evidence that DCC altered the incidence of neonatal hypoglycaemia compared to ECC.Although there are many other benefits of UCM and DCC, more high-quality studies are needed to enable reliable conclusions about their effect on hypoglycaemia.

Fig. 1
Fig. 1 PRISMA flow diagram of search process

Fig. 11 Fig. 12
Fig. 11 Effect of delayed cord clamping on breastfeeding at hospital discharge

Fig. 15
Fig. 15 Effect of delayed cord clamping on length of hospital stay

Table 2
Summary of neurodevelopmental outcomes Figures in brackets are age at follow up assessment

Reduced mild to moderate impairment with intervention No significant difference in mild to moderate impairment with intervention
Fig. 14 Effect of delayed cord clamping on neonatal mortality (at hospital discharge)

Table 3
GRADE summary findings table for umbilical cord milking outcome/s CI confidence interval, MD mean difference, RR risk ratio Explanations a Downgraded one level for risk of bias due to moderate risk of bias for this outcome b Downgraded one level for imprecision due to wide CI and low sample size

Table 4
GRADE summary findings table for delayed cord clamping outcomesCI confidence interval, DCC Delayed cord clamping, ECC Early cord clamping, MD mean difference, NICU Neonatal intensive care unit, RCT Randomised controlled trial, RR risk ratio Explanations a Downgraded one level for risk of bias due to moderate risk of bias for this outcome b Downgraded one level for imprecision due to wide CI and low sample size c Downgraded one level for heterogeneity (large I 2 and low p-value) d Downgraded one level for imprecision due to wide CI e Downgraded two levels for imprecision due to small sample size and only one study